Through collaborative work over the past 20 years, we have discovered that mutations in the TRPV4 gene cause two allelic neuromuscular disorders, scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot- Marie-Tooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type IIC (HMSN IIC)). Both SPSMA and CMT2C are characterized by peripheral axonal neuropathy. The pathogenesis of the axonal degeneration underlying these allelic disorders is not known. The TRPV4 gene encodes a transient receptor potential (TRP) cation channel, subfamily V, member 4 (TRPV4), a known Ca2+-permeable, non-selective cation channel. Our preliminary studies indicate that the SPSMA- and CMT2C-linked mutant TRPV4 channels have remarkably increased open probability to Ca2+, leading to an increased intracellular Ca2+ concentration when these channels are expressed in transfected tumor cell lines. These data suggest a potentially pathogenic role for abnormal changes in intracellular Ca2+ concentration in axonal degeneration. To date, 11 different mutations have been found in 24 unrelated families and isolated cases with variant forms of axonal neuropathies. Because the TRPV4-linked axonal neuropathies represent a newly identified group of neuromuscular disorders (TRPV4-channelopathies), many essential questions about their genetic and clinical features, and pathogenic mechanism remain to be addressed. In this application, we propose two closed related specific aims to address a few of the key unresolved issues, including (1) the overall picture of the genetics, clinical variants and potential genotype-phenotype correlation of the TRPV4-linked axonal neuropathies~ (II) the properties of mutant TRPV4 channels in motor neurons, the predominantly affected cell type in this group of disease. Successful completion of this project will provide much needed information for understanding not only the nature of these diseases, but also the molecular basis of the pathogenic mechanism, and therefore to provide a pathophysiological basis for rational therapies. This may be especially true when considering that the calcium channel activity of TRPV4 can be regulated by some known agonists and antagonists. Because TRPV4 can be activated by a wide range of physical and chemical stimuli, and increased Ca2+ influx has been associated with a number of other neurodegenerative diseases, the outcome of this project may also have important implications in the studies of other neurodegenerative diseases.